Cancer is caused, at least in part, by the mutation of specific genes. Understanding these genes and their function is crucial to the future development of cancer therapies and improved diagnostics. The objective of this application is to identify novel genes that are commonly mutated in human cancer, with a special emphasis on tumor suppressor genes in breast cancer. The major discovery tool will be representational difference analysis (RDA), a method that the investigators use to derive probes for the altered genomic DNA of tumors. They have used this method to identify over eight loci that are homozygously deleted in human breast cancer; and the PTEN tumor suppressor gene was identified in one of these. Nine other loci are under study. The method also will be used to detect rearrangements and viruses in tumors. In addition, they have developed new tools for transcriptional mapping and the genomic analysis that will be brought to bear on these problems. This project will interface with other ongoing projects and collaborations of the investigators' laboratory that aim to: 1) utilize large scale genomic sequencing and analysis for gene discovery; 2) understand the function of the genes mutated in cancer; 3) establish the clinical relevance of the genetic alterations at the loci the investigators discover; and 4) discover de novo germ line mutations causing inborn disorders in children.